A process for the preparation of 2-fluoro-3-chloronitrobenzene

Abstract

The application discloses a method for preparing 2-fluoro-3-chloronitrobenzene, which comprises the following steps: (1) mixing a crown ether and a quaternary ammonium salt ionic liquid uniformly according to a molar ratio of 1-2:1 to obtain a crown ether-quaternary ammonium salt ionic liquid composite catalyst; (2) adding 2,3-dichloronitrobenzene, anhydrous fluorinating reagent and the crown ether-quaternary ammonium salt ionic liquid composite catalyst obtained in the step (1) into a reactor, heating to 150-210 DEG C under the protection of inert gas, and fully reacting under the condition that the rotating speed is 600-1000 rpm to generate 2-fluoro-3-chloronitrobenzene. The application has the advantages of mild reaction condition, short reaction time, high yield and purity of the final product, and is a suitable industrialized synthesis method.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing 2-fluoro-3-chloronitrobenzene. BACKGROUND

[0002] 2-fluoro-3-chloronitrobenzene (CAS 392-75-8) as an important pharmaceutical intermediate, has key application value in the field of quinolone antibacterial drug synthesis. The specific halogen substitution pattern in its molecular structure can significantly affect the construction of the pharmacophore group of downstream products, for example, in the synthesis of the third generation of fluoroquinolones, Ofloxacin and Lomefloxacin, this compound can participate in the cyclization reaction as a core skeleton precursor. In addition, the chemical activity of its nitro functional group makes it exhibit unique synthon function in the synthesis route of anticancer drugs (such as topoisomerase inhibitors).

[0003] The existing industrial synthesis process mainly has the following technical routes:

[0004] (1) Nitration synthesis method: 2-fluoro-3-chlorobenzene is used as the starting material, and the target product is prepared by electrophilic substitution reaction in a mixed acid system (H2SO4 / HNO3, v / v = 3:1). This process has the following technical defects: a) Strongly corrosive medium requires the use of special reaction equipment such as Hastelloy C-276, significantly increasing CAPEX; b) Nitration reaction is highly exothermic (ΔH ≈ -210 kJ / mol), requiring a multi-stage cooling system to maintain the reaction temperature at 5 ± 1℃, with the risk of thermal runaway; c) Isomer separation requires multi-stage crystallization purification, and the product yield is limited.

[0005] (2) Halogen exchange method: based on the nucleophilic aromatic substitution reaction of 2,3-dichloronitrobenzene and fluorinating reagent. Zhu Zhihua et al. [Zhu Zhihua, Xu Peiruo, Yan Zhiguang, et al. Synthesis of 2,3,4-trifluoronitrobenzene from 2,3-dichloronitrobenzene [J]. Journal of East China University of Technology: Natural Science Edition, 1998,

[0006] 24(6):6.DOI:CNKI:SUN:HLDX.0.1998-06-003.]Using finely ground KF, tetramethylammonium chloride as phase transfer catalyst, 3-chloro-4-fluoro-nitrobenzene was synthesized from 3,4-dichloronitrobenzene (DCNB) under solvent-free condition, the purity of the target product was 95% and the yield was 75.3% under the condition of 175℃ for 10h. Li Huiping (Li Huiping. Research on synthesis process of 3-chloro-4-fluoro-nitrobenzene from 3,4-dichloronitrobenzene[D]. Zhengzhou University, 2003. DOI:10.7666 / d.y524178.) used high-activity potassium fluoride obtained by recrystallization method, cetyltrimethylammonium bromide (CTMAB) as phase transfer catalyst, 3-chloro-4-fluoro-nitrobenzene was synthesized from 3,4-dichloronitrobenzene (DCNB) under solvent-free condition, the optimum process conditions were as follows: raw material ratio: n(KF):n(DCNB) = 1.2-1.25:1, n(CTMAB):n(DCNB) = 0.06-0.07:1, stirring speed: 900-950 rpm, fluorination reaction temperature: 140-150℃, fluorination reaction time: 12h, under the above conditions, the yield of fluorination product 3-chloro-4-fluoro-nitrobenzene could reach 92.23%. The above-mentioned synthesis method of 3-chloro-4-fluoro-nitrobenzene needs to obtain high-activity potassium fluoride by recrystallization activation of potassium fluoride, which has the problems of high energy consumption and cost (recrystallization needs multiple heating, dissolution and cooling, and the heat cycle energy consumption is extremely high), difficult waste liquid treatment (such as residual metal ions in the crystallization mother liquor, which needs to be matched with an electrodialysis or ion exchange system), complex process control (such as crystallization kinetics limitation and impurity co-crystallization risk, etc.), and is not suitable for industrial large-scale production; or the yield is poor.

[0007] Therefore, it is urgent to develop a high-efficiency phase transfer catalytic system suitable for polysubstituted nitroarene system, and to establish a green and safe synthesis process of 2-fluoro-3-chloronitrobenzene with high yield, which has become a technical bottleneck to be broken through in the field. The present application successfully realizes the synergistic regulation of reaction activity and regioselectivity by constructing a new crown ether-quaternary ammonium salt ionic liquid composite catalytic system, which has significant environmental and economic benefits. SUMMARY

[0008] The purpose of the present application is to provide a green and safe, short reaction time, high yield, and suitable for industrial production method for preparing 2-fluoro-3-chloronitrobenzene.

[0009] In order to achieve the above-mentioned purpose of the application, the following technical solutions are adopted:

[0010] A method for preparing 2-fluoro-3-chloronitrobenzene, comprising the following steps:

[0011] (1) mixing crown ether and quaternary ammonium salt ionic liquid in a molar ratio of 1-2:1 to obtain a crown ether-quaternary ammonium salt ionic liquid composite catalyst;

[0012] (2) adding 2,3-dichloronitrobenzene, anhydrous fluorination reagent and the crown ether-quaternary ammonium salt ionic liquid composite catalyst obtained in step (1) into a reactor, heating to 150-210°C under inert gas protection, and fully reacting under the condition of a rotation speed of 600-1000 rpm to generate 2-fluoro-3-chloronitrobenzene.

[0013] The present application finds that the crown ether and quaternary ammonium salt ionic liquid are first made into a crown ether-quaternary ammonium salt ionic liquid composite catalyst for the fluorination reaction of 2,3-dichloronitrobenzene, and the crown ether and quaternary ammonium salt ionic liquid exhibit a synergistic effect, which can shorten the reaction time and significantly improve the purity and yield of the target product 2-fluoro-3-chloronitrobenzene.

[0014] As a preference, the quaternary ammonium salt ionic liquid is selected from one or more of trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt ([N 1112 ]NTf2), benzyl triethylamine chloride salt ([Nbz222]Cl), triethylbutylammonium bis(trifluoromethylsulfonyl) imide salt ([N2224]NTf2), butyl triethyl quaternary ammonium hydrogen sulfate salt ([N 2224 ]HSO4), butyl triethyl quaternary ammonium p-toluene sulfonate salt ([N 2224 ]Ps), butyl triethyl quaternary ammonium tetrafluoroborate ([N 2224 ]BF4).

[0015] As a preference, the crown ether is selected from one of 18-crown-6, 15-crown-5, 12-crown-4, and dibenzo-18-crown-6.

[0016] As a preference, the molar ratio of 2,3-dichloronitrobenzene, fluorination reagent and crown ether-quaternary ammonium salt ionic liquid composite catalyst is 1:0.9-1.2:0.03-0.1, more preferably 1:1:0.09-0.10, and the molar number of the crown ether-quaternary ammonium salt ionic liquid composite catalyst is based on the total molar number of crown ether and quaternary ammonium salt ionic liquid.

[0017] As a preference, the reaction temperature is 120-180°C, more preferably 150-180°C, and further more preferably 180°C.

[0018] As a preference, the reaction time is 6-12 hours, more preferably 6-7 hours, and further more preferably 6 hours.

[0019] The present application particularly preferably has a reaction temperature of 180°C and a reaction time of 6 hours.

[0020] The anhydrous fluorinating agent can be an inorganic fluorinated salt, hydrofluoric acid or an organic fluorinated compound; preferably potassium fluoride or cesium fluoride, and most preferably potassium fluoride. The anhydrous fluorinating agent used in the present application is commercially available and has a purity of ≥ 99% and a particle size of 300 mesh or more.

[0021] Preferably, the method for preparing 2-fluoro-3-chloronitrobenzene further comprises the following UV-ozone (UV-O3) synergistic treatment step:

[0022] The anhydrous fluorinating agent is treated with ozone under UV irradiation, and after sufficient treatment at room temperature, vacuum drying is performed, and then the obtained fluorinating agent is sealed and stored in an inert gas atmosphere; the fluorinating agent treated in this step is used in the reaction of step (2) above.

[0023] Further preferably, in the UV-ozone (UV-O3) synergistic treatment step, the UV irradiation uses UV light with a wavelength of 10-400 nm (preferably 10-380 nm), and the UV light intensity is controlled at 20,000-30,000 mW / m 2 , the ozone flow rate is 5-20 g / h, and the treatment time is 2-6 h.

[0024] Further preferably, in the UV-ozone (UV-O3) synergistic treatment step, the vacuum drying conditions are: vacuum drying at 100-150°C for 2-6 h.

[0025] The present application finds that UV-ozone (UV-O3) synergistic treatment of the fluorinating agent can significantly improve the surface activity of the fluorinating agent, and under the synergistic action of the fluorinating agent and the crown ether-quaternary ammonium salt ionic liquid composite catalyst, the purity and yield of the target product 2-fluoro-3-chloronitrobenzene are significantly improved.

[0026] Compared with the prior art, the present application has the following innovations and advantages:

[0027] 1. The present application does not require the addition of toxic solvents, and does not require desolventization during synthesis, is green and environmentally friendly, and simplifies the operation process.

[0028] 2. The crown ether-quaternary ammonium salt ionic liquid composite catalyst used in the present application can complete the reaction at a relatively low temperature, the reaction conditions are mild, the reaction time is short, and the yield and purity of the final product are high, making it a suitable industrial synthesis method. DETAILED DESCRIPTION

[0029] The present application will be described in detail below with specific examples, but it should not be understood as limiting the scope of protection of the present application, but only for further illustration of the present application. Those skilled in the art can make adjustments based on the above content.

[0030] Unless otherwise indicated, conventional conditions are used in the embodiments of the present application, or the conditions recommended by the manufacturer are used. Unless otherwise indicated, the reagents or instruments used are conventional products that can be obtained by conventional technical means or by purchase on the market.

[0031] The novel crown ether-quaternary ammonium salt ionic liquid composite catalytic system in the embodiments of the present application is obtained by uniformly mixing crown ether and quaternary ammonium salt ionic liquid according to a certain molar ratio.

[0032] The potassium fluoride used in the embodiments of the present application is commercially available anhydrous potassium fluoride with a purity of ≥99% and a particle size of 300 mesh or more.

[0033] Example 1

[0034] The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is put into a three-necked flask, and then potassium fluoride (5.81 g, 0.1 mol) and a novel crown ether-quaternary ammonium salt ionic liquid composite catalytic system (trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt ([N 1112 ]NTf2) (1.84 g, 0.005 mol), 18-crown-6 ether (1.23 g, 0.005 mol) are added, nitrogen is introduced for protection, the temperature is increased to 180°C, the rotation speed is 1000 rpm / min, and reflux reaction is carried out for 6 hours. After the reaction is completed, water is added to precipitate the product, inorganic salts are filtered, the filtrate is collected, and trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt and 18-crown-6 ether are recovered by distillation under reduced pressure. The unreacted raw materials and the generated product are analyzed by using a GC-9800 type gas chromatograph, a 2% OV-17 / Chromosorb W-AW-DMCS packed column is used, the column temperature is 180°C, the vaporization chamber temperature is 210°C, the detection chamber temperature is 210°C, and through chromatographic analysis, the yield of 2-fluoro-3-chloronitrobenzene is 82.5%, and the purity is 90.8%.

[0035] Example 2

[0036] The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is put into a three-necked flask, then potassium fluoride (5.81 g, 0.1 mol) and a new crown ether-quaternary ammonium salt ionic liquid composite catalytic system (benzyl triethylamine chloride salt ([Nbz222]Cl) (1.14 g, 0.005 mol), 18-crown-6 (1.23 g, 0.005 mol) are added, nitrogen is introduced for protection, the temperature is raised to 180°C, the rotation speed is 1000 rpm / min, and reflux reaction is carried out for 6 hours. After the reaction is completed, water is added to precipitate the product, the inorganic salt is filtered, the filtrate is collected, and benzyl triethylamine chloride salt and 18-crown-6 are recovered by reduced pressure distillation. Chromatographic analysis shows that the yield of 2-fluoro-3-chloronitrobenzene is 86.2% and the purity is 92.3%.

[0037] Example 3

[0038] (1) UV-ozone (UV-O3) synergistic treatment: first, potassium fluoride is placed in a U-PVC reaction tube, an ozone generator is used to generate ozone, and the ozone is introduced from the bottom of the reactor, the ozone generation amount is 10 g / h, a UV lamp is placed at the center position of the reactor, the wavelength of the UV light is 254 nm, and the UV light intensity is controlled at 26001 mW / m 2 The treatment is carried out at room temperature for 3 hours, and the product is treated at a constant temperature of 110°C in a vacuum drying box for 6 hours, and then is sealed and stored in a nitrogen-filled dryer for standby.

[0039] The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is put into a three-necked flask, then potassium fluoride (5.81 g, 0.1 mol) and a new crown ether-quaternary ammonium salt ionic liquid composite catalytic system (benzyl triethylamine chloride salt ([Nbz222]Cl) (1.14 g, 0.005 mol), 18-crown-6 (1.23 g, 0.005 mol) are added, nitrogen is introduced for protection, the temperature is raised to 180°C, the rotation speed is 1000 rpm / min, and reflux reaction is carried out for 6 hours. After the reaction is completed, water is added to precipitate the product, the inorganic salt is filtered, the filtrate is collected, and benzyl triethylamine chloride salt and 18-crown-6 are recovered by reduced pressure distillation. Chromatographic analysis shows that the yield of 2-fluoro-3-chloronitrobenzene is 86.2% and the purity is 92.3%. 1112 ]NTf2), 1.84 g, 0.005 mol), 18-crown-6 (1.23 g, 0.005 mol) are added, nitrogen is introduced for protection, the temperature is raised to 180°C, the rotation speed is 1000 rpm / min, and reflux reaction is carried out for 6 hours. After the reaction is completed, water is added to precipitate the product, the inorganic salt is filtered, the filtrate is collected, and benzyl triethylamine chloride salt and 18-crown-6 are recovered by reduced pressure distillation. Chromatographic analysis shows that the yield of 2-fluoro-3-chloronitrobenzene is 86.2% and the purity is 92.3%.

[0040] Example 4

[0041] (1) A certain amount of potassium fluoride is accurately weighed with an electronic balance, put into a beaker, a proper amount of deionized water is added, and a stirrer is used to stir to completely dissolve it, so as to prepare a potassium fluoride solution with a certain concentration.

[0042] (2) Filtration to remove impurities: The prepared potassium fluoride solution is filtered through a filter to remove insoluble impurities that may be present, ensuring the purity of the solution.

[0043] (3) Spray drying treatment: The filtered potassium fluoride solution is poured into the feed tank of the spray dryer. The general inlet air temperature can be set at 200°C, and the outlet air temperature at 120°C. The spray dryer is turned on, and the solution is atomized into fine droplets, which are fully contacted with hot air, and the water rapidly evaporates. Potassium fluoride is precipitated in powder form and collected at the bottom of the drying chamber or in the cyclone separator.

[0044] (4) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is added to a three-necked flask, followed by potassium fluoride (5.81 g, 0.1 mol) and a new crown ether-quaternary ammonium salt ionic liquid composite catalyst (trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt ([N 1112 ]NTf2) (1.84 g, 0.005 mol), 18-crown-6 (1.23 g, 0.005 mol), nitrogen protection, temperature rise to 180°C, rotation speed 1000 rpm / min, reflux reaction for 6 hours. After the reaction is completed, add water to precipitate the product, filter the inorganic salt, collect the filtrate, and recover trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt and 18-crown-6 by reduced pressure distillation. Chromatographic analysis shows that the yield of 2-fluoro-3-chloronitrobenzene is 89.6%, and the purity is 94.2%.

[0045] Example 5

[0046] (2) UV-ozone (UV-O3) synergistic treatment: First, potassium fluoride is placed in a U-PVC reaction tube, an ozone generator is used to generate ozone, which is introduced from the bottom of the reactor, the ozone generation amount is 10 g / h, a UV lamp is placed at the center position of the reactor, the wavelength of the UV light is 254 nm, and the intensity of the UV light is controlled at 26001 mW / m 2 The treatment is carried out at room temperature for 3 hours, and the product is treated in a vacuum drying oven at 110°C for 6 hours, and then sealed and stored in a nitrogen-filled dryer for standby.

[0047] (3) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is added to a three-necked flask, followed by potassium fluoride (5.81 g, 0.1 mol) and a new crown ether-quaternary ammonium salt ionic liquid composite catalyst (trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt ([N 1112]NTf2) (1.84 g, 0.005 mol), 18-crown-6 (1.23 g, 0.005 mol), nitrogen protection, temperature to 180 °C, speed 1000 rpm / min, reflux reaction for 6 hours. After the reaction, add water to precipitate the product, filter the inorganic salt, collect the filtrate, and recover the trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt and 18-crown-6 by vacuum distillation. The yield of 2-fluoro-3-chloronitrobenzene is 98.3% by chromatographic analysis, and the purity is 99.1%.

[0048] By comparing Example 3 with Example 5, it can be seen that the ultraviolet-ozone (UV-O3) synergistic treatment of potassium fluoride can significantly improve the yield and purity of the fluorination reaction product.

[0049] Example 6

[0050] (1) Ultraviolet-ozone (UV-O3) synergistic treatment: first put potassium fluoride in the U-PVC reaction tube, use an ozone generator to generate ozone and introduce it from the bottom of the reactor, the ozone generation amount is 10 g / h, the ultraviolet lamp is placed in the center of the reactor, the ultraviolet light wavelength is 254 nm, and the ultraviolet light intensity is controlled at 26001 mW / m 2 , and the product is treated in a vacuum drying oven at 110 °C for 6 hours, and is sealed and stored in a nitrogen-filled dryer for standby.

[0051] (2) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is put into a three-necked flask, and then potassium fluoride (5.81 g, 0.1 mol) treated by ultraviolet-ozone (UV-O3) synergistic treatment is added. New crown ether-quaternary ammonium salt ionic liquid composite catalytic system (trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt ([N 1112 ]NTf2) (1.84 g, 0.005 mol), 18-crown-6 (1.23 g, 0.005 mol), nitrogen protection, temperature to 180 °C, speed 1000 rpm / min, reflux reaction for 6 hours. After the reaction, add water to precipitate the product, filter the inorganic salt, collect the filtrate, and recover the trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt and 18-crown-6 by vacuum distillation. The yield of 2-fluoro-3-chloronitrobenzene is 98.3% by chromatographic analysis, and the purity is 99.1%.

[0052] Example 7

[0053] (1) UV-ozone (UV-O3) synergistic treatment: first, the potassium fluoride was placed in the U-PVC reactor tube, using ozone generator to generate ozone, and from the bottom of the reactor, the ozone generation amount was 10 g / h, the UV lamp was placed in the center of the reactor, the UV light wavelength was 254 nm, the UV light intensity was controlled at 26001 mW / m 2 The product was treated at room temperature for 3 h, and then treated at 110°C in a vacuum drying box for 6 h. The product was sealed and stored in a nitrogen-filled dryer for later use.

[0054] (2) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) was added to a three-necked flask, and then the potassium fluoride (5.81 g, 0.1 mol) treated by UV-ozone (UV-O3) synergistic treatment was added to the new crown ether-quaternary ammonium salt ionic liquid composite catalytic system (trimethylethylammonium bis(trifluoromethylsulfonyl) imidate ([N 1112 ]NTf2) (1.84 g, 0.005 mol), and dibenzo-18-crown-6 (1.80 g, 0.005 mol) were added. Nitrogen was introduced for protection, the temperature was raised to 120°C, the rotation speed was 1000 rpm / min, and the reaction was refluxed for 6 hours. After the reaction was completed, water was added to precipitate the product, the inorganic salt was filtered, the filtrate was collected, and trimethylethylammonium bis(trifluoromethylsulfonyl) imidate and dibenzo-18-crown-6 were recovered by reduced pressure distillation. The yield of 2-fluoro-3-chloronitrobenzene was 90.3% and the purity was 99.1% by chromatographic analysis.

[0055] Example 8

[0056] (1) UV-ozone (UV-O3) synergistic treatment: first, the potassium fluoride was placed in the U-PVC reactor tube, using ozone generator to generate ozone, and from the bottom of the reactor, the ozone generation amount was 10 g / h, the UV lamp was placed in the center of the reactor, the UV light wavelength was 254 nm, the UV light intensity was controlled at 26001 mW / m 2 The product was treated at room temperature for 3 h, and then treated at 110°C in a vacuum drying box for 6 h. The product was sealed and stored in a nitrogen-filled dryer for later use.

[0057] (2) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) was added to a three-necked flask, and then the potassium fluoride (5.81 g, 0.1 mol) treated by UV-ozone (UV-O3) synergistic treatment was added to the new crown ether-quaternary ammonium salt ionic liquid composite catalytic system (trimethylethylammonium bis(trifluoromethylsulfonyl) imidate ([N 1112(1) UV-O3 synergistic treatment: first, the potassium fluoride was placed in the U-PVC reactor tube, using ozone generator to produce ozone, and from the bottom of the reactor into the ozone generation amount of 10 g / h, the UV lamp was placed in the center of the reactor, the UV light wavelength was 254 nm, the UV light intensity was controlled at 26001 mW / m2, the reaction temperature was 150 °C, the rotation speed was 1000 rpm / min, and the reaction time was 6 h. After the reaction was completed, the product was precipitated by adding water, the inorganic salt was filtered, the filtrate was collected, and the trimethylethyl ammonium bis(trifluoromethyl sulfonyl) imide salt and the dibenzo-18-crown-6 were recovered by vacuum distillation. The yield of 2-fluoro-3-chloronitrobenzene was 95.2% by chromatographic analysis, and the purity was 98.9%.

[0058] Example 9

[0059] (1) UV-O3 synergistic treatment: first, the potassium fluoride was placed in the U-PVC reactor tube, using ozone generator to produce ozone, and from the bottom of the reactor into the ozone generation amount of 10 g / h, the UV lamp was placed in the center of the reactor, the UV light wavelength was 254 nm, the UV light intensity was controlled at 26001 mW / m 2 , and the reaction time was 6 h. After the reaction was completed, the product was precipitated by adding water, the inorganic salt was filtered, the filtrate was collected, and the trimethylethyl ammonium bis(trifluoromethyl sulfonyl) imide salt and the dibenzo-18-crown-6 were recovered by vacuum distillation. The yield of 2-fluoro-3-chloronitrobenzene was 95.2% by chromatographic analysis, and the purity was 98.9%.

[0060] (2) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) was added to a three-necked flask, and then potassium fluoride (5.81 g, 0.1 mol) treated by UV-O3 synergistic treatment was added. The new crown ether-quaternary ammonium salt ionic liquid composite catalytic system (trimethylethyl ammonium bis(trifluoromethyl sulfonyl) imide salt ([N 1112 ]NTf2) (1.84 g, 0.005 mol), dibenzo-18-crown-6 (1.80 g, 0.005 mol), nitrogen protection, temperature rise to 150 °C, rotation speed 1000 rpm / min, reflux reaction 4 h. After the reaction was completed, the product was precipitated by adding water, the inorganic salt was filtered, the filtrate was collected, and the trimethylethyl ammonium bis(trifluoromethyl sulfonyl) imide salt and the dibenzo-18-crown-6 were recovered by vacuum distillation. The yield of 2-fluoro-3-chloronitrobenzene was 75.2% by chromatographic analysis, and the purity was 99.2%.

[0061] Comparative Example 1

[0062] The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 19.2 g (0.1 mol) of 2,3-dichloronitrobenzene was added to a three-necked flask, followed by potassium fluoride (5.81 g, 0.1 mol) and 18-crown ether-6 (2.46 g, 0.01 mol). Nitrogen gas was introduced for protection, and the mixture was heated to 180 °C and refluxed at 1000 rpm / min for 6 hours. After the reaction was complete, water was added to precipitate the product. The inorganic salts were filtered off, and the filtrate was collected. 18-crown ether-6 was recovered by vacuum distillation. Chromatographic analysis showed that the yield of 2-fluoro-3-chloronitrobenzene was 20.7%, and the purity was 43.9%.

[0063] Comparative Example 2

[0064] The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is added to a three-necked flask, followed by potassium fluoride (5.81 g, 0.1 mol) and trimethylethylammonium bis(trifluoromethanesulfonyl)imine salt ([N... 1112 3.68 g (0.01 mol) of NTf2 was used under nitrogen protection, and the mixture was heated to 180 °C and refluxed at 1000 rpm for 6 hours. After the reaction was complete, water was added to precipitate the product, the inorganic salts were filtered off, the filtrate was collected, and the trimethylethylammonium bis(trifluoromethanesulfonyl)imine salt was recovered by vacuum distillation. Chromatographic analysis showed that the yield of 2-fluoro-3-chloronitrobenzene was 53.4%, and the purity was 76.8%.

[0065] The comparison between Example 3 and Comparative Examples 1 and 2 shows that the crown ether and quaternary ammonium salt ionic liquid in the crown ether-quaternary ammonium salt ionic liquid composite catalytic system have a synergistic effect. Compared with the crown ether and quaternary ammonium salt ionic liquid used alone, it can significantly improve the yield and purity of the fluorination reaction products.

[0066] Comparative Example 3

[0067] (1) Ultraviolet-ozone (UV-O3) synergistic treatment: First, potassium fluoride was placed in a U-PVC reaction tube, and ozone was generated using an ozone generator, which was introduced from the bottom of the reactor at a rate of 10 g / h. The ultraviolet lamp was placed in the center of the reactor, with an ultraviolet wavelength of 254 nm and an ultraviolet light intensity controlled at 2600 mW / m. 2 The product was treated at room temperature for 3 hours, and then kept at a constant temperature of 110°C for 6 hours in a vacuum drying oven. It was then sealed and stored in a nitrogen-filled desiccator for later use.

[0068] (2) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) is put into a three-necked flask, and then potassium fluoride (5.81 g, 0.1 mol) and trimethylethylammonium bis(trifluoromethanesulfonyl)imine salt ([N1112 ]NTf2)(3.68g, 0.01mol), nitrogen protection, temperature to 180℃, 1000 rpm / min, reflux reaction for 6 hours. After the reaction, add water to precipitate the product, filter the inorganic salt, collect the filtrate, and recover the trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt by distillation under reduced pressure. By chromatographic analysis, the yield of 2-fluoro-3-chloronitrobenzene is 74.2%, and the purity is 82.5%.

[0069] Comparative Example 4

[0070] (1) UV-ozone (UV-O3) synergistic treatment: first put potassium fluoride in the U-PVC reactor tube, use ozone generator to generate ozone, and introduce it from the bottom of the reactor, the ozone generation amount is 10 g / h, the ultraviolet lamp is placed in the center position of the reactor, the ultraviolet light wavelength is 254 nm, and the ultraviolet light intensity is controlled at 26001 mW / m 2 , and the product is treated in a vacuum drying box at 110℃ for 6 hours, and is sealed and stored in a nitrogen-filled dryer for standby.

[0071] (2) The preparation method of 2-fluoro-3-chloronitrobenzene is as follows: 2,3-dichloronitrobenzene (19.2g, 0.1mol) is put into a three-necked flask, then UV-ozone (UV-O3) synergistically treated potassium fluoride (5.81g, 0.1mol) and 18-crown-6 ether (2.46g, 0.01mol) are added, nitrogen protection, temperature to 180℃, 1000 rpm / min, reflux reaction for 6 hours. After the reaction, add water to precipitate the product, filter the inorganic salt, collect the filtrate, and recover 18-crown-6 ether by distillation under reduced pressure. By chromatographic analysis, the yield of 2-fluoro-3-chloronitrobenzene is 52.4%, and the purity is 68.6%.

[0072] From the comparison of Comparative Example 1 and Comparative Example 3, and Comparative Example 2 and Comparative Example 4, it can be seen that the UV-ozone (UV-O3) synergistic treatment of potassium fluoride can improve the yield and purity of the fluorination reaction product of the crown ether or quaternary ammonium salt ionic liquid as the catalyst to a certain extent, but it is still not ideal. However, in the case of crown ether-quaternary ammonium salt ionic liquid composite catalytic system, the UV-ozone (UV-O3) synergistic treatment of potassium fluoride can significantly improve the yield and purity of the fluorination product.

[0073] Comparative Example 5

[0074] 2-Fluoro-3-chloronitrobenzene was prepared as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) was put into a three-necked flask, then potassium fluoride (5.81 g, 0.1 mol) and tetramethylammonium chloride (0.55 g, 0.005 mol), 18-crown-6 ether (1.23 g, 0.005 mol) were added, and the reaction was carried out under nitrogen protection at 180 °C with a rotation speed of 1000 rpm / min for 6 h. After the reaction was completed, water was added to precipitate the product, and the inorganic salt was filtered. The filtrate was collected and tetramethylammonium chloride and 18-crown-6 ether were recovered by distillation under reduced pressure. The yield of 2-fluoro-3-chloronitrobenzene was 25.6% with a purity of 64.3% by chromatographic analysis.

[0075] Comparative Example 6

[0076] 2-Fluoro-3-chloronitrobenzene was prepared as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) was put into a three-necked flask, then potassium fluoride (5.81 g, 0.1 mol) and tetramethylammonium chloride (0.55 g, 0.005 mol), 18-crown-6 ether (1.23 g, 0.005 mol) were added, and the reaction was carried out under nitrogen protection at 180 °C with a rotation speed of 1000 rpm / min for 6 h. After the reaction was completed, water was added to precipitate the product, and the inorganic salt was filtered. The filtrate was collected and tetramethylammonium chloride and 18-crown-6 ether were recovered by distillation under reduced pressure. The yield of 2-fluoro-3-chloronitrobenzene was 25.6% with a purity of 64.3% by chromatographic analysis.

[0077] Comparative Example 7

[0078] 2-Fluoro-3-chloronitrobenzene was prepared as follows: 2,3-dichloronitrobenzene (19.2 g, 0.1 mol) was put into a three-necked flask, then potassium fluoride (5.81 g, 0.1 mol) and tetramethylammonium chloride (0.55 g, 0.005 mol), 18-crown-6 ether (1.23 g, 0.005 mol) were added, and the reaction was carried out under nitrogen protection at 180 °C with a rotation speed of 1000 rpm / min for 6 h. After the reaction was completed, water was added to precipitate the product, and the inorganic salt was filtered. The filtrate was collected and tetramethylammonium chloride and 18-crown-6 ether were recovered by distillation under reduced pressure. The yield of 2-fluoro-3-chloronitrobenzene was 25.6% with a purity of 64.3% by chromatographic analysis.

Claims

1. A process for the preparation of 2-fluoro-3-chloronitrobenzene, characterized in that: The method comprises the following steps: (1) mixing the crown ether and the quaternary ammonium salt ionic liquid uniformly according to a molar ratio of 1-2:1 to obtain a crown ether-quaternary ammonium salt ionic liquid composite catalyst; the quaternary ammonium salt ionic liquid is selected from one or more of trimethylethylammonium bis(trifluoromethylsulfonyl) imide salt, benzyl triethylamine chloride salt, and triethylbutylammonium bis(trifluoromethylsulfonyl) imide salt; and the crown ether is selected from one of 18-crown-6, 15-crown-5, 12-crown-4, and dibenzo-18-crown-6; (2) adding 2,3-dichloronitrobenzene, anhydrous fluorinating agent, and the crown ether-quaternary ammonium salt ionic liquid composite catalyst obtained in step (1) into a reactor, heating to 150-210 DEG C under protection of inert gas, and fully reacting under the condition of a rotation speed of 600-1000 rpm to generate 2-fluoro-3-chloronitrobenzene; the anhydrous fluorinating agent is anhydrous potassium fluoride with a purity of greater than or equal to 99% and a particle size of greater than or equal to 300 mesh; the molar ratio of the 2,3-dichloronitrobenzene, the fluorinating agent, and the crown ether-quaternary ammonium salt ionic liquid composite catalyst is 1:0.9-1.2:0.03-0.1, and the molar number of the crown ether-quaternary ammonium salt ionic liquid composite catalyst is based on the total molar number of the crown ether and the quaternary ammonium salt ionic liquid.

2. The method of claim 1, wherein: The preparation method further comprises the following step of ultraviolet-ozone synergistic treatment: under irradiation of ultraviolet light, the anhydrous fluorinating agent is treated by passing in ozone, vacuum dried after fully treating under ambient conditions, and then the obtained fluorinating agent is sealed and stored under an inert gas atmosphere; the fluorinating agent treated in this step is used in the reaction of step (2) above.

3. The method of claim 2, wherein: In the UV-ozone synergic treatment step, the UV light with wavelength of 10-400 nm is used, the UV light intensity is controlled at 20000-30000 mW / m 2 , the ozone input amount is 5-20 g / h, and the treatment time is 2-6 h.

4. The method according to any one of claims 1 to 3, characterized in that: The molar ratio of the 2,3-dichloronitrobenzene, the fluorinating agent, and the crown ether-quaternary ammonium salt ionic liquid composite catalyst is 1:1:0.09-0.

10.

5. The method according to any one of claims 1 to 3, characterized in that: The reaction temperature is 150-180 DEG C, and the reaction time is 6-7 hours.

6. The method of claim 5, wherein: The reaction temperature is 180 DEG C, and the reaction time is 6 hours.